Many compounds with in vivo effects of high interest for cosmetic formulations, e. g. antioxidants, are poorly soluble, which inhibits or excludes their use for cosmetic products. Examples are Rutin and Hesperidin, having antioxidant properties. The “natural” molecules possess highest activity, but they do not reach in vivo a sufficient effect because of their poor solubility. Therefore, one is forced to use derivatives which are biologically distinctly less efficient but are water-soluble or oil-soluble, and can therefore be dissolved in the water or oil phase of cosmetic preparations, e. g. cosmetic creams and lotions.
Another example is Resveratrol (3,4′,5-trihydroxystilbene), a polyphenol found for example in the skins of red grapes. Resveratrol has anti-infective, antioxidant and anti-inflammatory properties. In addition, it is collagen-protective. It supports existing collagen structures and inhibits collagen-degrading enzymes (Mizutani et. al, Biochem Biophys Res Commun. Jul. 21, 2000; 274 (1):61-7).
One approach for the use of such compounds is their incorporation in polymeric or hydrophobic microparticles or nanoparticles. One commercial product is NanoSal™ Resveratrol, proprietary technology of the company Salvona Consumer Care (U.S. Pat. No. 7,067,152 and U.S. Pat. No. 6,979,440). The particles are offered as system enabling the release of the active over an extended period of time, which means a prolonged release system. However, such systems are contra productive because the prolonged release slows down the uptake by the skin due to concentrations of resveratrol in the water phase being below its saturation solubility. The molecules are captured in the particle matrix. Just the opposite would be desirable, to have a system releasing the active very fast leading to saturation or ideally supersaturation of the water phase. The supersaturation leads to an increased concentration gradient between the topical formulation and the skin and, thus, promoting the penetration of the active into the skin.
A pharmaceutical formulation approach to formulate poorly soluble drugs is nanocrystals. Drug nanocrystals are crystals with a size of a few nanometers up to 1000 nanometer. They can be prepared by bottom-up technologies and top-down technologies (Müller, R. H., Akkar, A., Drug nanocrystals of poorly soluble drugs, in: Encyclopedia of Nanoscience and Nanotechnology (H. S. Nalwa, ed.), American Scientific Publishers, 627-638, 2004, Müller, R. H., Böhm, B. H. L., Grau, M. J., Nanosuspensions—a formulation approach for poorly soluble and poorly bioavailable drugs, in: Handbook of Pharmaceutical Controlled Release Technology (Wise, D., ed.), 345-357, 2000). Bottom-up technologies are precipitation, the drug is dissolved in a solvent and this solution subsequently poured into a non-solvent leading to the so-called hydrosols (Sucker, et al., GB Patent 2200048, 1988; GB Patent 2269536, 1994) (product NanoMorph™ by the company Soliqs, belonging to Abbott). In the top-down technologies, one starts from larger sized particle powders, diminution by several wet milling techniques leads to nanocrystals. In general the drug powder is dispersed in an aqueous or non-aqueous dispersion medium, containing a stabilizer (surfactant or polymeric stabilizer). This macro-suspension is subsequently milled for example by using a pearl mill (Liversidge, et al., U.S. Pat. No. 5,145,684, 1992) or passing the suspension through a high pressure homogenizer (Müller et al., PCT Application PCT/EP1995/004401, 1995, U.S. Pat. No. 5,858,410, 1999, PCT Application PCT/EP2000/006535, 2000). The nanosuspension is used as it is, for example for intravenous injection or, alternatively the dispersion medium is removed to obtain a dry nanocrystal powder, which is further processed for example to tablets.
The literature describes intensively the use of drug nanocrystals only for pharmaceutical formulations, i. e. for oral administration and for intravenous injection. After oral administration the bioavailability can be enhanced (Liversidge, et al., U.S. Pat. No. 5,145,684, 1992, G. G. Liversidge and K. C. Cundy, “Particle Size Reduction for Improvement of Oral Bioavailability of Hydrophobic Drugs: I. Absolute Oral Bioavailability of Nanocrystalline Danazol in Beagle Dogs,” Int. J. Pharm. 125 (1), 91-97 (1995).), intravenous injection of drug nanosuspensions is able to reduce undesired toxic side effects of drugs. For example, the nephrotoxicity of the drug Itraconazole could be reduced distinctly by injection of Itraconazole nanosuspension ([1] J. Heykants, et al., “The Pharmacokinetics of Itraconazole in animals and man”, Recent Trends in the Discovery, Development and Evolution of Anitfungal Agents, R. A. Fromtling (Ed) 1987. [2] D. Andes, et al., “In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis”, Antimicrob Agents and Chemotherapy, April 2003, 1179-1186, [3] Rabinow et el., Enhanced Efficacy of Nanoedge Itraconazole Nanosuspension in an immunosuppressed rat model infected with an Itraconazole-resistant C. Albicans Strain, Abstract of AAPS Annual meeting in Salt Lake City, Utah, 2003). A recent review of the drug nanocrystal technology is presented by Müller et al. (Keck, C. M., Müller, R. H., Eur. J. Pharm. Biopharm. 62, 3-16, 2006). However, there is no data published proving that drug nanocrystals are beneficial when used in topical pharmaceutical formulations applied to the skin. Especially there are no hints that the biological activity of drugs in the skin is increased. Furthermore, there are no reports for cosmetic actives about increase of biological activity when the actives are used in a nanocrystalline form.